NLRP3 Inflammasome in Parkinson's Disease

Target Validation, 2015

Objective/Rationale: † † † † † ††The goal of this proposal is to validate the NLRP3 inflammasome as a therapeutic target in Parkinsonís disease. Unlike circulating inflammatory mediators whose complex functions are notoriously difficult to target, inflammasomes are intracellular initiators of inflammation. By validating the activity of the NLRP3 inflammasome in central nervous system tissues from Parkinsonís patients, we will inform emerging clinical trials of small molecule inflammasome inhibitors designed to suppress neuroinflammation during the progression of disease.

Project Description:To assess directly the activity of inflammasomes in the central nervous system (CNS) of Parkinsonís disease patients, we will evaluate post-mortem tissues obtained at the Dartmouth-Hitchcock Medical Center and through collaboration with the Wisconsin Parkinsonís Association. Using matched cryopreserved and fixed tissue specimens obtained from patients with Parkinsonís disease we will conduct a dual biochemical and immunohistologic evaluation designed to characterize cellular and molecular manifestations of NLRP3 inflammasome activity. In so doing, we will also determine the cellular origins of NLRP3 activity in CNS tissues thereby providing a comprehensive characterization of NLRP3 activity in sporadic Parkinsonís disease.

Relevance to Diagnosis/Treatment of Parkinsonís Disease:Neuroinflammation is now recognized as a hallmark of Parkinsonís disease, but this discovery has not yet resulted in the advancement of anti-inflammatory therapies designed to modify progressive neurodegeneration. By characterizing the activity of the NLRP3 inflammasome in Parkinsonís disease, we hope to provide a new platform from which to design, monitor and evaluate new diagnostic indicators and novel therapeutic targets.

Anticipated Outcome: † † † † †Our goal is to block the progression of Parkinsonís disease by suppressing neuroinflammation and the associated neurodegeneration prior to the development of debilitating motor and non-motor symptomology. Based upon new and exciting preliminary data, we anticipate this study will identify NLRP3 activation as a key pathologic mechanism in Parkinsonís disease and thereby catapult forward the development of anti-inflammasome therapeutics for clinical trials in patients with Parkinsonís disease.

FINAL OUTCOME

Most molecules that promote inflammation do that by stimulating the cells from the outside. Unlike these traditional inflammatory mediators, inflammasomes initiate the inflammation from the inside the cell. One of the inflammasomes, NLRP3, initiates and perpetuates inflammation in response to cellular stress. In this study, we analyzed tissue samples and genetic data obtained from people with Parkinson's disease (PD) to determine whether the NLRP3 inflammasome represents a therapeutic target in PD. We found that, in some nerve cells, the levels of NLRP3 are higher in people with Parkinson's than in healthy people. This finding is important because it clarifies how distressed neurons contribute to brain inflammation in PD. To further investigate whether NLRP3 plays a role in PD, we analyzed genetic data from the Parkinson's Progression Markers Initiative (PPMI), a landmark study to find biomarkers -- disease indicators -- of Parkinson's disease. We identified a genetic abnormality in the NLRP3 gene whose presence was associated with a reduced risk of developing PD. Our studies clarify the role of NLRP3 in PD. They also provide a platform for improving our understanding of PD-associated inflammation and developing new therapeutic approaches aimed at modulating the activity of NLRP3 in Parkinson's disease.